Many drugs are introduced into the systemic circulation by intravenous (IV) injection to ensure rapid and complete bioavailability, and to transport them to their therapeutic target in the body. However, clinical use of these drugs may be limited if at their target dose the drugs are insoluble or poorly soluble in water in the desired injection volume. Such compounds are termed “hydrophobic”, “lipophilic”, or in their most difficult form, “amphiphobic”.
If the drug at its target dose is not soluble in the desired injection volume and formulation vehicle, it becomes necessary to solubilize the drug to proceed with product development. The solubilization techniques for injectable formulations include pH adjustment, mixed aqueous/organic cosolvents, organic solvent mixtures, cyclodextrin complexation, liposomes, polymeric gels, and combinations of such techniques. Strickley, R. Pharm. Res. 21, 201-230, 2004. Ionizable drug molecules can be solubilized to the desired concentration by pH adjustment if the drug's pKa is sufficiently different from the formulation pH value. The solution pH can be controlled by either selecting the salt form of the drug, strong acids/bases, or a buffer. Where a buffer is used, the buffer concentration must be high enough to maintain the desired pH, but must be balanced by in vivo tolerability considerations. Napaporn, J. et al. Pharm. Dev. Tech. 5: 123-130 (2000). When pH adjustment alone is insufficient to achieve the desired concentration of the drug in solution, the combination of an aqueous solution and a water-soluble organic solvent/surfactant can be used in injectable formulations. Lee, Y-C. et al. Intl. J. Pharm. 253: 111-119 (2003). Moderately hydrophobic drugs can be solubilized by incorporating them into liposomes, closed spherical vesicles composed of outer lipid bilayer membranes and an inner aqueous core. In some instances the drug becomes encapsulated or intercalated within the liposome. Hydrophobic drugs can also be solubilized by liposomes if the drug molecule becomes an integral part of the lipid bilayer membrane by dissolving in the lipid portion of the lipid bilayer.
The drug is considered “challenging” if the drug is not solubilized by pH modification, cosolvents, complexation or combinations of these approaches. Surfactants, such as Cremophor EL, Cremophor RH 60, and polysorbate 80, can be used to solubilize some of the most water-insoluble drugs. These formulations can be prepared to contain concentrated drug solutions in an organic solvent that is diluted prior to intravenous administration. However, the limitations of these approaches include the possibility of precipitation of the drug, pain, inflammation, hemolysis, phlebitis, as well as deleterious effects on drug stability.